Long-range communication between transmembrane- and nucleotide-binding domains does not depend on drug binding to mutant P-glycoprotein

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Bonito, CA (Author) Other; Ferreira, RJ (Author) Other; Ferreira, MJU (Author) Other; Gillet, JP (Author) Other; Natalia N D S Cordeiro (Author) FCUP; dos Santos, DJVA (Author) Other

Journal

Title: Journal of Biomolecular Structure and Dynamics

Pages: 1-10

ISSN: 0739-1102

Publisher: Taylor & Francis

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-00Y-1ZR

DOI: 10.1080/07391102.2023.2181633

Abstract (EN): In this study, the impact of four P-gp mutations (G185V, G830V, F978A and Delta F335) on drug-binding and efflux-related signal-transmission mechanism was comprehensively evaluated in the presence of ligands within the drug-binding pocket (DBP), experimentally related with changes in their drug efflux profiles. The severe repacking of the transmembrane helices (TMH), induced by mutations and exacerbated by the presence of ligands, indicates that P-gp is sensitive to perturbations in the transmembrane region. Alterations on drug-binding were also observed as a consequence of the TMH repacking, but were not always correlated with alterations on ligands binding mode and/or binding affinity. Finally, and although all P-gp variants holo systems showed considerable changes in the intracellular coupling helices/nucleotide-binding domain (ICH-NBD) interactions, they seem to be primarily induced by the mutation itself rather than by the presence of ligands within the DBP. The data further suggest that the changes in drug efflux experimentally reported are mostly related with changes on drug specificity rather than effects on signal-transmission mechanism. We also hypothesize that an increase in the drug-binding affinity may also be related with the decreased drug efflux, while minor changes in binding affinities are possibly related with the increased drug efflux observed in transfected cells.Communicated by Ramaswamy H. Sarma

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10